Ether of n-propanol amine

ABSTRACT

.[.Ethers.]. .Iadd.An ether .Iaddend.of n-propanolamine, preparation thereof and .[.their.]. .Iadd.its .Iaddend.use in treatment of cardiovascular conditions.

This invention relates to .[.ethers.]. .Iadd.an ether .Iaddend.ofn-propanolamine, to the preparation thereof and to the use thereof.

The present invention provides an ether of an n-propanolamine having the.[.general.]. formula: ##STR1## .[.in which A is a tertiary aliphatic,cycloaliphatic or heterocyclic amino group, R is a straight or branchedchain lower alkyl group or an aralkyl group, Ar is an aromatic group andAr¹ is an aromatic or heterocyclic group,.]. and addition salts thereofwith pharmacologically acceptable acids.

.[.When Ar and Ar¹ are both aromatic groups they may be like or unlike.Ar and Ar¹ may both be monocyclic aromatic groups and Ar¹ may be aheteromonocyclic group which may contain a nuclear nitrogen atom with orwithout an additional nuclear hetero atom..].

The .[.compounds.]. .Iadd.compound .Iaddend.of the present invention.[.are.]. .Iadd.is .Iaddend.useful as .[.medicaments.]. .Iadd.amedicament .Iaddend.especially in the treatment of cardiovascularconditions.

In earlier patent applications we have described compounds having thegeneral formula: ##STR2## in which A .Iadd.is substantially a tertiaryaliphatic, cycloaliphatic or heterocyclo amino group .Iaddend.and R.[.have substantially the same meanings as in formula I above,.]..Iadd.is substantially a straight or branched chain lower alkyl group,.Iaddend.and X respectively represents the following groupings in thevarious cases: ##STR3## .Iadd.wherein Ar is an aromatic group and Ar¹ isan aromatic or heterocyclic group. .Iaddend.

Moreover, compounds having the following general formula are alreadyknown for their properties as antihistamines: ##STR4## in which A hasthe same meaning as .[.in the general formulae I and II.]..Iadd.indicated .Iaddend.above, whilst Ar and Ar¹ are aromatic groups.(Ehrhart/Ruschig Arzneimittel I, pages 208-210).

The .[.compounds.]. .Iadd.compound .Iaddend.according to the presentinvention having the .[.general.]. formula I, .[.are.]. .Iadd.is.Iaddend.manifestly different from any of these groups of compounds.

The .[.compounds.]. .Iadd.compound .Iaddend.of the present invention maybe prepared from .Iadd.an .Iaddend.amino .[.alcohols.]. .Iadd.alcohol.Iaddend.having the .[.general.]. formula: ##STR5## .[.in which A and Rare as defined above in connection with formula I..].

In the first step of such preparation, the amino .[.alcohols.]..Iadd.alcohol .Iaddend.(IV), which .[.are.]. .Iadd.is a .Iaddend.known.[.materials.]. .Iadd.material.Iaddend., and .[.are.]. .Iadd.is.Iaddend.described inter alia in Belgium Pat. No. 718 425, .[.are.]..Iadd.is .Iaddend.treated with thionyl chloride dissolved in a suitablesolvent such as chloroform in order to obtain the corresponding chloro.[.compounds.]. .Iadd.compound .Iaddend.having the .[.general.].formula: ##STR6## The latter .[.compounds are.]. .Iadd.compound is.Iaddend.then condensed with .[.amines.]. .Iadd.an amine .Iaddend.havingthe .[.general.]. formula ##STR7## which .[.have.]. .Iadd.has.Iaddend.previously been converted to .[.their.]. .Iadd.its.Iaddend.sodium .[.derivatives.]. .Iadd.derivative .Iaddend.by reactionwith sodium amide, to obtain the .[.compounds.]. .Iadd.compound.Iaddend.of the present invention.

The invention also includes the addition salts of the .[.compounds.]..Iadd.compound .Iaddend.having the .[.general.]. formula I withpharmaceutically acceptable organic and inorganic acids such ashydrochloric acid and fumaric acid.

.[.As an.]. .Iadd.An .Iaddend.example of the process of the invention.[.there.]. will now be described .Iadd.for .Iaddend.the synthesis of.[.1-(3-isobutoxy-2-(phenylbenzyl)-amino)-propyl-pyrrolidino-hydrochloride(Compound No. 1)..]. .Iadd.1-iso-butoxy-2-pyrrolidino-3-N-benzylanilinopropane hydrochloride (Compound 1). .Iaddend. ##STR8## First step

Preparation of 1-(3-isobutoxy-2-chloro)propyl pyrrolidine ##STR9## 345ml of thionyl chloride dissolved in 345 ml of chloroform are added, dropby drop, to 275 g of 1(3-isobutoxy-2-hydroxy)-propyl-pyrrolidinedissolved in 350 ml of chloroform, while maintaining the temperature atapproximately 45° C. The reaction mixture is heated to reflux until gasis no longer evolved. The chloroform and the excess of thionyl chlorideare removed under reduced pressure. The residue is poured on to 400 g ofcrushed ice. The reaction mixture is rendered alkaline with soda and theresulting mixture is extracted twice with 250 ml of diethyl ether. Thecombined ethereal extracts are dried over anhydrous sodium sulphate.After evaporation of the solvent the residue is distilled under reducedpressure: 220 g of product are obtained having the following properties:

Boiling point=96° C./3 mm, n_(D) ²⁴° C. =1,4575,

Second step

Main product

23.4 g of sodium amide is added little by little to a solution of 92 gof N-benzylaniline in 500 ml of anhydrous xylene. The reaction mixtureis then heated at 130° to 135° C. for 6 hours.

Whilst maintaining the temperature at 110° C., 110 g of the product ofthe first step dissolved in 150 ml of xylene is added and the productheated for 6 hours at 120° C.

The product having been allowed to cool to ambient temperature, 200 mlof cold water are added. The organic phase is separated and extractedwith an aqueous solution of hydrochloric acid.

After twice washing with 100 ml of diethyl ether, the aqueous phase ismade alkaline with 50% caustic soda solution. The liberated base istwice extracted with 150 ml of diethyl ether. After the ether has beenevaporated, the residue is distilled under reduced pressure and hasBpt=184° C./0.1 mm, n_(D) ²⁰ =1.5538.

77 g of the pure base in the form of a viscous liquid is thus obtained.

The hydrochloride, which is prepared in conventional manner, has amelting point of 128° C.

    ______________________________________                                        Analysis  C%         H%         N%                                            ______________________________________                                        Calculated:                                                                             71.52      8.75       6.95                                          Found:    71.20      9.01       6.93                                          ______________________________________                                    

.[.Table I which follows sets out a series of products according to thepresent invention which were obtained using the foregoing method butsubstituting the appropriate intermediates containing the desired groupsR and A and Ar and Ar¹ respectively..].

    .[.TABLE I                                                                    __________________________________________________________________________    COM-                              Melting                                                                            ANALYSIS                               POUND                             Points of                                                                          C%      H%      N%                     No.  Ar    Ar.sup.1                                                                            R        A       Salts °C.                                                                   Theory                                                                            Found                                                                             Theory                                                                            Found                                                                             Theory                                                                            Found              __________________________________________________________________________          ##STR10##                                                                           ##STR11##                                                                           ##STR12##                                                                              ##STR13##                                                                            Hydro- chloride 128°                                                        71.52                                                                             71.20                                                                             8.75                                                                              9.01                                                                              6.95                                                                              6.93               2                                                                                   ##STR14##                                                                           ##STR15##                                                                           ##STR16##                                                                              ##STR17##                                                                            Fumarate 150°                                                               67.08                                                                             66.90                                                                             7.66                                                                              7.20                                                                              8.69                                                                              8.75               3                                                                                   ##STR18##                                                                           ##STR19##                                                                           ##STR20##                                                                              ##STR21##                                                                            Fumarate 98°                                                                69.39                                                                             69.46                                                                             8.31                                                                              8.34                                                                              5.77                                                                              5.72               4                                                                                   ##STR22##                                                                           ##STR23##                                                                          CH.sub.3                                                                                ##STR24##                                                                            Fumarate 155°                                                               68.16                                                                             68.42                                                                             7.32                                                                              7.30                                                                              6.35                                                                              6.31               5                                                                                   ##STR25##                                                                           ##STR26##                                                                           ##STR27##                                                                              ##STR28##                                                                            Fumarate 195°                                                               67.44                                                                             67.90                                                                             7.68                                                                              7.76                                                                              5.61                                                                              5.64               6                                                                                   ##STR29##                                                                           ##STR30##                                                                           ##STR31##                                                                              ##STR32##                                                                            Hydro- chloride 133°                                                        74.55                                                                             74.05                                                                             7.82                                                                              7.40                                                                              6.21                                                                              6.14 .].           __________________________________________________________________________

The pharmacological activity of the .[.compounds.]. .Iadd.compound.Iaddend.of the invention in the cardiovascular field was determined onthe dog in the manner described below:

An incision is made in the right-hand chest wall of an animal, which hasbeen anaesthetised with chloralose and given artificial respiration, toenable the blood from the venus sinus to be drawn off and the apparatusrequired to record the following parameters to be inserted in position:

a. Output of the coronary sinus;

b. P_(v) O₂ of the blood from the coronary sinus; and

c. Amplitude of the contractions of the right ventricule.

At the same .Iadd.time .Iaddend.there were also measured:

d. Arterial pressure in a main carotid artery; and

e. The rate of heart-beat determined cardiotachometrically.

Table II which follows records the determinations made of the variousparameters, the results being expressed as a maximum percentagevariation relative to the pre-treatment values.

                                      TABLE II                                    __________________________________________________________________________         DOSE                                                                     COM- mg/kg                                                                             NUMBER        RATE OF       ARTERIAL                                                                             AMPLITUDE OF                      POUND                                                                              (intra-                                                                           OF    CORONARY                                                                              HEART-BEAT                                                                            P.sub.V O.sub.2                                                                     PRESSURE                                                                             VENTRICULAR                       No.  venous)                                                                           ANIMALS                                                                             OUTPUT %                                                                              %       %     %      CONTRACTION                       __________________________________________________________________________                                                %                                  1   2.5 7     +51.2   -28.6   +119.2                                                                              -39.8  -0.7                                   5   7     +36.9   -31.8   +120.8                                                                              -40.2  -22.3                             .[.2 5   3     +55     -28     +71   -43    -25.5.].                          .[.3 5   4     +117.8  -19.2   +158  -30.5  -3.].                             .[.4 5   4     +110.5  -14.5   -56   -26    +17.5.].                          .[.5 5   3     +24     -3.5    +11.6 -15    +1.5.].                           __________________________________________________________________________

These results show that, taken as a whole, the .[.products.]..Iadd.product .Iaddend.under examination .[.have.]. .Iadd.has.Iaddend.the ability to increase the output of cornary blood, to reducethe rate of heart beat and especially.[., with the exception of compoundNo. 4,.]. to increase the oxygen content of the venous cardiac blood.The latter action is demonstrated by an excess in the supply of oxygenrelative to the requirements of the myocardium. The arterial pressure isalso lowered for a short time. .[.In most cases there.]. .Iadd.There.Iaddend.is little alteration in the ventricular inotropism.

Particular note should be taken.[., in the case of compound No. 1,.]. ofthe very considerable increase in the oxygen content of the venouscardiac blood in relation to the increase in coronary output, which maybe simply attributed to the improved circulation of the blood. Theextremely slow rate of heart-beat brought about by the productscertainly plays an important role in this respect.

It then seemed interesting.[., using compound No. 1,.]. to seek theexistence of an action on the β-adrenergic receptors in the manneroutlined below:

A stimulating electrode was placed in position on the right stellarganglion of dogs anaesthetised as described above and for which therewere recorded:

a. The arterial pressure,

b. Ventricular inotropism (the amplitude of contraction of the rightventricle), and

c. The rate of heart-beat.

The chest of the animals were not open and they were breathing freely.

The β-adrenergic receptors, both cardiac and vascular, were stimulatedby electrical stimulation of the right stellar ganglion or byintravenous injection with isoprenaline (5 μg/kg). The measurements weretaken both before and after administration of compound No. 1 by theintravenous route in a dose of 5 mg/kg bodyweight.

The following Table III gives the average percentage inhibition of thecardiovascular effects of isoprenaline and of the cardiac effects of thestimulation of the right stellar ganglion.

                  TABLE III                                                       ______________________________________                                                   Number                   Positive                                             of     Hypo-   Rate of   inotropic                                            Animals                                                                              tension Heart-beat                                                                              effect                                    ______________________________________                                        ISOPRENALINE 4        -54%    -32.7%  -46.5%                                  .[.(5 ug/kg.]..Iadd.(5 μg/kg.Iaddend.                                      intravenous)                                                                  STIMULATION OF                                                                THE RIGHT                                                                     STELLAR                                                                       GANGLION     3                -30%    -21.3%                                  ______________________________________                                    

These results show that a partial inhibiting effect is achieved asregards the β-adrenergic receptors at the cardiovascular level oftreatment.

In conclusion, it is apparent that the .[.members of the series ofcompounds possess.]. .Iadd.compound possesses .Iaddend.a distinctcardio-vascular activity which is manifested by an improvement incirculation by the enhanced oxygenation of the myocardium in consequenceof a slow rate of heart-beat.

In addition to the general properties .[.of the compounds of the presentinvention,.]. compound No. 1 is also of interest in that it alsopossesses inhibiting effects with respect to the stimulation of theβ-adrenergic receptors.

The pharmacological activities of .[.the compounds having the generalformula.]. .Iadd.compound .Iaddend.I thus .[.enable their.]..Iadd.enables its .Iaddend.application in human therapy to beanticipated, as .[.medicaments.]. .Iadd.a medicament .Iaddend.intendedfor treating particularly:

Myocardiac anoxaemia,

Coronary deficiencies, angina pectoris,

Infarction of the myocardium, and

Cardiac deficiencies associated with coronary circulatory trouble.

When admixed with the usual excipients, .[.they.]. .Iadd.it .Iaddend.maybe administered orally or rectally, in daily doses of between 100 and800 mg.

What we claim is: .[.1. An ether of n-propanolamine having theformula.]. ##STR33## .[.wherein A is morpholino, pyrrolidino, piperidyl,and di-lower-alkyl amino, R is a straight or branched chain lower alkyl,or benzyl, Ar is aryl and Ar¹ is aryl or pyridyl, and pharmacologicallyacceptable salts thereof..]. .[.2. The ether of claim 1 in which A ispyrrolidino, R is isobutyl and Ar and Ar¹ are both phenyl, and thehydrochloride thereof..]. .[.3. The ether of claim 1 in which A ispyrrolidino, R is isobutyl, Ar is phenyl and Ar¹ is 2-pyridyl, and theacid fumarate thereof..]. .[.4. The ether of claim 1 in which A isdiethylamino, R is an isobutyl and Ar and Ar¹ are both phenyl, and theacid fumarate thereof..]. .[.5. The ether of claim 1 in which A ismorpholino, R is isobutyl and Ar and Ar¹ are both phenyl and the acidfumarate thereof..]. .[.6. The ether of claim 1 in which A is piperidyl,R is benzyl and Ar and Ar¹ are both phenyl and the hydrochloridethereof..]..Iadd.
 7. An ether having the formula .Iaddend. ##STR34##.Iadd.and pharmaceutically acceptable acid addition salts thereof..Iaddend. .Iadd.
 8. An ether according to claim 7 wherein the acidaddition salt is the hydrochloride or the acid fumarate. .Iaddend.